Knee osteoarthritis (KOA) is one of the most prevalent causes of pain and disability, and its incidence continues to increase as the elderly and obese populations grow. While most KOA patients report reduced pain and improved function after Total Knee Arthroplasty (TKA), approximately 20% of them continue to experience significant pain and disability even years post-TKA. The factors underlying inter-individual differences in susceptibility to post-TKA pain are largely unknown. In this project, we will measure levels of the translocator protein (TSPO), a protein upregulated in activated glia, in the brains of patients undergoing TKA and evaluate TSPO's role in post-TKA pain. TSPO functions to limit the magnitude of glia-mediated inflammatory responses, thereby promoting the return to pre-injury status and recovery from pain. Thus, interindividual differences in TSPO expression may explain why a small but substantial percentage of OA patients do not fully heal following TKA. We will perform brain scans in 110 KOA patients (pre-surgically, 1-to-2 weeks post-TKA and, in a subset of patients also 12 months post-TKA), and in 25 healthy volunteers (once). All patients will be also evaluated clinically 1 year post-TKA. Brain scans will be performed using integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and the recently developed [11C]PBR28 radioligand, which binds to TSPO. MR data collected simultaneously to PET data will allow us to perform an MR-based motion correction of the PET data (a novel procedure that significantly improves the fidelity, sensitivity, and specificity of PT data). First, we will test the hypothesis that pre-surgically KOA patients will demonstrate higher [11C]PBR28 brain binding than healthy controls, which will be evidence of KOA-related glial activation. Then we will evaluate the hypothesis that TKA itself leads to an additional increase of [11C]PBR28 brain binding, which will be evidence of TKA-related glial activation. We also hypothesize that at 1-year post-TKA, [11C]PBR28 binding will still be elevated in patients still experiencing significant pain and disability, whereas it will be reduced to the levels of the contrl subjects in recovered patients. Finally, we will test the hypothesis that [11C]PBR28 binding pre- and peri-surgically will predict occurrence of long-term postsurgical pain 1 year after TKA. In particular, given the proposed anti-inflammatory and pain-protective role of TSPO, we will test the hypothesis that low pre-surgical / peri-surgical TSPO levels will predict higher likelihood of developing post-TKA pain. The identification of a role of glia and its modulation in the development and maintenance of persistent pain and pain-related disability following TKA will have important practical implications for the management of post-operative pain, and the development of tailored preventive interventions focused on glial modulation.